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Clinical Pediatric Endocrinology : Case... 2022In Japan, a pituitary-extracted human GH (phGH), Crescormon®, was approved for the treatment of pituitary dwarfism in 1975. The Study Group of Pituitary Dysfunction was... (Review)
Review
In Japan, a pituitary-extracted human GH (phGH), Crescormon®, was approved for the treatment of pituitary dwarfism in 1975. The Study Group of Pituitary Dysfunction was organized by the Ministry of Health and Welfare (MHW) in 1973 and prepared the "Diagnostic Handbook: Pituitary Dwarfism" guidelines in 1974. Eligibility assessments for phGH treatment were conducted by the research group on pituitary dwarfism (later the Foundation for Growth Science [FGS] GH Treatment Eligibility Assessment Committee); however, there were 200-300 patients on the waiting list. GH treatment has been financially supported by the Grant-in-Aid Program for Chronic Diseases in Childhood, MHW, since 1974. In 1984, phGH was discontinued in the United States due to reports of the onset of Creutzfeldt-Jakob disease in patients treated with phGH. Japan approved the use of methionyl hGH in 1986 and recombinant hGH in 1988. As a result, the phGH disappeared from the market. The role of the Eligibility Assessment Committee of the FGS shifted to the provision of second opinions about diagnoses and treatment appropriateness. Since then, the indications for GH treatment of pediatric growth disorders have expanded to include other pediatric growth disorders such as Turner syndrome, achondroplasia/hypochondroplasia, etc.
PubMed: 35002062
DOI: 10.1297/cpe.2021-0044 -
Human Reproduction (Oxford, England) Oct 2023In modern post-transition societies, we are reproducing later and living longer. While the impact of age on female reproductive function has been well studied, much less...
In modern post-transition societies, we are reproducing later and living longer. While the impact of age on female reproductive function has been well studied, much less is known about the intersection of age and male reproduction. Our current understanding is that advancing age brings forth a progressive decline in male fertility accompanied by a reduction in circulating testosterone levels and the appearance of age-dependent reproductive pathologies including benign prostatic hypertrophy and erectile dysfunction. Paternal ageing is also associated with a profound increase in sperm DNA damage, the appearance of multiple epigenetic changes in the germ line and an elevated mutational load in the offspring. The net result of such changes is an increase in the disease burden carried by the progeny of ageing males, including dominant genetic diseases such as Apert syndrome and achondroplasia, as well as neuropsychiatric conditions including autism and spontaneous schizophrenia. The genetic basis of these age-related effects appears to involve two fundamental mechanisms. The first is a positive selection mechanism whereby stem cells containing mutations in a mitogen-activated protein kinase pathway gain a selective advantage over their non-mutant counterparts and exhibit significant clonal expansion with the passage of time. The second is dependent on an age-dependent increase in oxidative stress which impairs the steroidogenic capacity of the Leydig cells, disrupts the ability of Sertoli cells to support the normal differentiation of germ cells, and disrupts the functional and genetic integrity of spermatozoa. Given the central importance of oxidative stress in defining the impact of chronological age on male reproduction, there may be a role for antioxidants in the clinical management of this process. While animal studies are supportive of this strategy, carefully designed clinical trials are now needed if we are to realize the therapeutic potential of this approach in a clinical context.
Topics: Animals; Male; Female; Semen; Reproduction; Aging; Spermatozoa; Mutation
PubMed: 37568254
DOI: 10.1093/humrep/dead157 -
The American Journal of Nursing Mar 2022The Food and Drug Administration has granted accelerated approval to vosoritide (Voxzogo) to treat children ages five years and older with achondroplasia who still have...
The Food and Drug Administration has granted accelerated approval to vosoritide (Voxzogo) to treat children ages five years and older with achondroplasia who still have open epiphyses.Children prescribed vosoritide should have a meal and 240 to 300 mL of fluid in the hour prior to drug administration to prevent hypotensive episodes.
Topics: Achondroplasia; Child; Child, Preschool; Humans; United States; United States Food and Drug Administration
PubMed: 35200181
DOI: 10.1097/01.NAJ.0000822964.26069.7e -
Proceedings of the National Academy of... Jul 2022The C-natriuretic peptide (CNP) analog vosoritide has recently been approved for treatment of achondroplasia in children. However, the regimen requires daily...
The C-natriuretic peptide (CNP) analog vosoritide has recently been approved for treatment of achondroplasia in children. However, the regimen requires daily subcutaneous injections in pediatric patients over multiple years. The present work sought to develop a long-acting CNP that would provide efficacy equal to or greater than that of vosoritide but require less frequent injections. We used a technology for half-life extension, whereby a drug is attached to tetra-polyethylene glycol hydrogels (tetra-PEG) by β-eliminative linkers that cleave at predetermined rates. These hydrogels-fabricated as uniform ∼60-μm microspheres-are injected subcutaneously, where they serve as a stationary depot to slowly release the drug into the systemic circulation. We prepared a highly active, stable CNP analog-[Gln]CNP-38-composed of the 38 C-terminal amino acids of human CNP-53 containing Asn to Gln substitutions to preclude degradative deamidation. Two microsphere [Gln]CNP-38 conjugates were prepared, with release rates designed to allow once-weekly and once-monthly administration. After subcutaneous injection of the conjugates in mice, [Gln]CNP-38 was slowly released into the systemic circulation and showed biphasic elimination pharmacokinetics with terminal half-lives of ∼200 and ∼600 h. Both preparations increased growth of mice comparable to or exceeding that produced by daily vosoritide. Simulations of the pharmacokinetics in humans indicated that plasma [Gln]CNP-38 levels should be maintained within a therapeutic window over weekly, biweekly, and likely, monthly dosing intervals. Compared with vosoritide, which requires ∼30 injections per month, microsphere [Gln]CNP-38 conjugates-especially the biweekly and monthly dosing-could provide an alternative that would be well accepted by physicians, patients, and patient caregivers.
Topics: Achondroplasia; Animals; Child; Delayed-Action Preparations; Drug Development; Humans; Hydrogels; Injections, Subcutaneous; Mice; Microspheres; Natriuretic Peptide, C-Type
PubMed: 35858423
DOI: 10.1073/pnas.2201067119 -
Wiener Medizinische Wochenschrift (1946) Apr 2020Achondroplasia is the most common form of disproportionate short stature. A dominantly inherited FGFR3 mutation permanently activates the fibroblast growth factor... (Review)
Review
Achondroplasia is the most common form of disproportionate short stature. A dominantly inherited FGFR3 mutation permanently activates the fibroblast growth factor receptor 3 (FGFR3) and its downstream mitogen-activated protein kinase (MAPK) signalling pathway. This inhibits chondrocyte differentiation and puts a break on growth plate function, in addition to causing serious medical complications such as foramen magnum and spinal stenosis and upper airway narrowing. A great deal has been learned about complications and consequences of FGFR3 activation and management guidance is evolving aimed to reduce the increased mortality and morbidity in this condition, particularly deaths from spinal cord compression and sleep apnoea in infants and small children. To date, no drugs are licensed for treatment of achondroplasia. Here, we report on the various substances in the drug development pipeline which target elements in molecular disease mechanism such as FGF (fibroblast growth factor) ligands, FGFR3, MAPK signalling as well as the C‑type natriuretic peptide receptor NPR‑B (natriuretic peptide receptor B).
Topics: Achondroplasia; Cell Differentiation; Child; Humans
PubMed: 32144686
DOI: 10.1007/s10354-020-00741-6 -
Neurosurgery Clinics of North America Jan 2022Achondroplasia is the most common of skeletal dysplasias and is caused by a defect in endochondral bone formation. In addition to skeletal deformities, patients with... (Review)
Review
Achondroplasia is the most common of skeletal dysplasias and is caused by a defect in endochondral bone formation. In addition to skeletal deformities, patients with achondroplasia possess significant abnormalities of the axial skeleton, including small skull base with a narrowed foramen magnum and small vertebral bodies with shortened pedicles. Consequently, patients with achondroplasia are at risk of several severe neurologic conditions, such as cervicomedullary compression, spinal stenosis, and hydrocephalus, which frequently require the attention of a neurosurgeon. This article provides an updated review on the neurosurgical evaluation and care of children with Achondroplasia.
Topics: Achondroplasia; Child; Constriction, Pathologic; Foramen Magnum; Humans; Hydrocephalus; Infant; Spinal Stenosis
PubMed: 34801138
DOI: 10.1016/j.nec.2021.09.003 -
Ceskoslovenska Patologie 2023We present a comprehensive review dealing with rare genetic skeletal disorders. More than 400 entities are included in the latest classification. The most severe or... (Review)
Review
We present a comprehensive review dealing with rare genetic skeletal disorders. More than 400 entities are included in the latest classification. The most severe or lethal phenotypes are identifiable in the prenatal period and the pregnancy can be terminated. Perinatal autopsy and posmortem X-rays are crucial in providing a definitive diagnosis. The number of cases confirmed by genetic testing is increasing. We report our own experience with genetic skeletal disorders based on 41 illustrative fetal and neonatal cases which we encountered over a 10-year period. Thanatophoric dysplasia and osteogenesis imperfecta represent approximately half of the cases coming to autopsy. Achondrogenesis type 2 and hypochondrogenesis, short-rib dysplasia, chondrodysplasia punctata, campomelic dysplasia and achondroplasia are less common. Skeletal dysplasias with autosomal recessive inheritance are the least frequent, e.g. perinatally lethal hypophophatasia, achondrogenesis type 1A, diastrophic dysplasia/atelosteogenesis type 2 or mucolipidosis type 2 (I cell disease).
Topics: Pregnancy; Female; Humans; Osteochondrodysplasias; Thanatophoric Dysplasia; Campomelic Dysplasia; Receptor, Fibroblast Growth Factor, Type 3; Fetus
PubMed: 37468326
DOI: No ID Found -
Current Opinion in Endocrinology,... Feb 2020To discuss treatments used to enhance growth in pediatric patients with short stature. (Review)
Review
PURPOSE OF REVIEW
To discuss treatments used to enhance growth in pediatric patients with short stature.
RECENT FINDINGS
New data confirm the known efficacy of recombinant human growth hormone (rhGH) in growth hormone deficiency (GHD) and idiopathic short stature. The latest data from the Safety and Appropriateness of Growth hormone Treatment in Europe cohort did not indicate a long-term risk of malignancy in those treated for isolated GHD, but possibly increased risk in those with other diagnoses. Recombinant human insulin-like growth factor 1 is effective in treating patients with pregnancy-associated plasma protein A2 deficiency. Gonadotropin-releasing hormone agonists or aromatase inhibitor treatment to delay puberty remains controversial. They are more likely to augment adult height if combined with rhGH treatment in children already receiving rhGH. Preliminary data indicate that recombinant C-type natriuretic peptide (CNP) is safe in children and increases growth velocity upon 42 months of treatment in achondroplasia.
SUMMARY
Recent data confirms previous data on rhGH efficacy and safety. Therapies to delay growth plate closure have greatest efficacy to augment height if combined with GH in select diagnoses. Recombinant CNP holds promise as a medical treatment for short stature associated with achondroplasia.
Topics: Adult; Body Height; Child; Dwarfism, Pituitary; Endocrinology; Europe; Growth Disorders; Hormone Replacement Therapy; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Puberty; Recombinant Proteins
PubMed: 31789832
DOI: 10.1097/MED.0000000000000513 -
Frontiers in Pediatrics 2022In recent years, new therapies for the treatment of rare pediatric bone disorders have emerged, guided by an increasing understanding of the genetic and molecular... (Review)
Review
In recent years, new therapies for the treatment of rare pediatric bone disorders have emerged, guided by an increasing understanding of the genetic and molecular etiology of these diseases. Herein, we review three such disorders, impacted by debilitating deficits in bone mineralization or cartilage ossification, as well as the novel disease-modifying drugs that are now available to treat these conditions. Specifically, we discuss asfotase alfa, burosumab-twza, and vosoritide, for the treatment of hypophosphatasia, X-linked hypophosphatemia and achondroplasia, respectively. For each skeletal disorder, an overview of the clinical phenotype and natural history of disease is provided, along with a discussion of the clinical pharmacology, mechanism of action and FDA indication for the relevant medication. In each case, a brief review of clinical trial data supporting drug development for each medication is provided. Additionally, guidance as to drug dosing and long-term monitoring of adverse events and pediatric efficacy is presented, to aid the clinician seeking to utilize these novel therapies in their practice, or to become familiar with the healthcare expectations for children receiving these medications through specialized multidisciplinary clinics. The availability of these targeted therapies now significantly augments treatment options for conditions in which past therapy has relied upon less specific, symptomatic medical and orthopedic care.
PubMed: 36304528
DOI: 10.3389/fped.2022.1012816 -
Clinical Pediatric Endocrinology : Case... 2022The health-related quality of life is reduced in patients with achondroplasia (ACH) and hypochondroplasia (HCH); however, the detailed inconveniences in the daily living...
The health-related quality of life is reduced in patients with achondroplasia (ACH) and hypochondroplasia (HCH); however, the detailed inconveniences in the daily living and individual adaptations have not been elucidated. This study aimed to evaluate the inconvenience and adaptation in patients with ACH/HCH. A cross-sectional study was conducted in patients with ACH/HCH aged 20 yr or older. Questionnaires were sent to 567 patients (described 86) with a medical history at the co-authors' institutions or who were registered at the patients' association with ACH in Japan. The questionnaire included a free description format for the inconveniences and adaptations in daily living; a content analysis was performed. The recorded inconveniences included 148 physical, 84 mental, and 52 social problems. Patients who underwent spine surgery had significantly more recorded physical problems than those who did not (p < 0.05). Pain and numbness were significantly higher in patients aged ≥ 50 yr (p < 0.05). The 160 and 1 adaptations were for physical and social problems, respectively. No patient adaptation was found for mental health problems. Individual adaptations by ACH/HCH patients can improve only some aspects of physical and social problems. Multilateral social support is needed to resolve patients' issues.
PubMed: 35002064
DOI: 10.1297/cpe.2021-0043